Training Plan: This proposal describes a mentored 5-year research training program for the development of an independent investigator in anesthetic mechanisms. The Principal Investigator is an Assistant Professor of Anaesthesia at Harvard Medical School (HMS) and a faculty anesthesiologist at Massachusetts General Hospital (MGH), with a background in anesthetic pharmacology and electrophysiology. His mentor, Dr. Emery N. Brown, is Warren M. Zapol Professor of Anaesthesia at HMS, Professor of Computational Neuroscience in the Dept. of Brain and Cognitive Sciences at the Massachusetts Institute of Technology (MIT), and Professor of Health Sciences and Technology at HMS and MIT. With the Mentored Clinical Scientist Research Career Development Award, the Principal Investigator will acquire new knowledge and skills in systems neuroscience sufficient to develop an independent research program. He will take courses in the Dept. of Brain and Cognitive Sciences at MIT, and his research training will take place in laboratories at MGH, MIT, and the University of California, San Diego. The long-term objective of this proposal is to prepare the Principal Investigator for a successful independent career studying anesthetic mechanisms using a systems neuroscience approach. Research Plan: Accumulating evidence suggests that ascending arousal pathways in the brain promote emergence from general anesthesia (GA). Elucidating these mechanisms may lead to improved pharmacological control over the arousal states of anesthetized patients, better treatments for emergence delirium, better neurophysiological monitors to detect intraoperative awareness, and ultimately a safer and more efficient practice of anesthesiology. Our preliminary data suggest that pharmacological activation of dopaminergic and cholinergic arousal circuits during steady-state exposure to isoflurane produce distinct arousal states that are characterized by different behavioral and neurophysiological endpoints. The goal of this project is to elucidate the roles of dopaminergic and cholinergic arousal circuits in promoting emergence from GA. Using a combination of pharmacological and brain microstimulation techniques, we will probe the behavioral and neurophysiological correlates of actively induced emergence from GA. PUBLIC HEALTH RELEVANCE: Many of the clinical problems related to emergence from general anesthesia (GA) have not been solved because the neural mechanisms underlying emergence have not been elucidated. The goal of this project is to elucidate the roles of dopaminergic and cholinergic arousal circuits in promoting emergence from GA. Knowledge of these mechanisms may lead to advances in clinical care including novel methods to control the arousal states of patients, better treatments for emergence delirium, and improved neurophysiological monitors that optimize anesthetic dosing and protect patients from intraoperative awareness.